Medical diagnostic imaging has evolved as an important non-invasive tool for the evaluation of pathological and physiological processes. Presently, nuclear magnetic resonance imaging (“MRI”) and computerized tomography (“CT”) are two of the most widely used imaging modalities. Although both MRI and CT can be performed without the administration of contrast agents, the ability of many contrast enhancement agents to enhance the visualization of internal tissues and organs has resulted in their widespread use.
Proton MRI is based on the principle that the concentration and relaxation characteristics of protons in tissues and organs can influence the intensity of a magnetic resonance image. Contrast enhancement agents that are useful for proton MRI effect a change in the relaxation characteristics of protons, which can result in image enhancement and improved soft-tissue differentiation. Different classes of proton MR imaging agents include paramagnetic metal chelates and nitroxyl spin labeled compounds.
Detection and monitoring of tumor growth and remission is vital for the effective diagnosis and treatment of cancer. Current methods for detecting tumor growth and regression using CT scan, positron emission tomography (“PET”), optical imaging and MRI are limited in their ability to distinguish between normal and tumor tissue. Additionally, the ability to image the vasculature within in a tissue and occlusion of that vasculature finds application in a variety of different scenarios. Vascular occlusion imaging is presently limited by a variety of obstacles, one of which is the inability to selectively image occlusions over other tissues and structures. Further, there is no currently available method of monitoring internal wound healing, nor is there an adequate method of monitoring angiogenic activity in tumor and non-tumor tissue.
The use of envirosensitive liposomes in hyperthermia therapy is a promising approach to targeting a tumor or other tissue. Broadly, envirosensitive liposomes comprise a formulation adapted to lose structural integrity under certain environmental conditions. For example, thermosensitive liposomes lose structural integrity within a given temperature range. Alternatively, the envirosensitive liposome can be a radiation sensitive liposome, which is formulated to lose its structural integrity when contacted with a particular wavelength range of electromagnetic radiation. When an envirosensitive liposome, such as a thermosensitive or a radiation sensitive liposome, loses its structural integrity, the contents of the liposome are released.
One consideration with respect to the use of envirosensitive liposomes as a delivery vehicle (e.g. for a therapeutic compound) is the ability to target the liposomes to a desired location, such as a tumor. Targeting liposomes, both envirosensitive and insensitive species, has been a subject of research for some time. Various approaches have been taken, including the formation of immunoliposomes, which comprise, for example, an antibody or a fragment of an antibody (see, e.g., Sullivan & Huang, (1985) Biochim. Biophys. Acta 812(1): 116-126; Perlaky et al., (1996) Oncol. Res. 8(9): 363-369).
Liposome targeting, however, depends in part on how stably the liposomes administered to a subject circulate through the circulatory system in the normal physiological environment and how effectively the liposomes release their content (e.g. a drug) at a particular desired site (e.g. a tumor). In the case of some thermosensitive liposomes targeting has been problematic. For example, the liposomes described by Yatvin et al. (Yatvin et al., (1978) Science 202: 1290) release only a small amount of the drug at the temperature of hyperthermia. Other liposomes have been observed to release the drug at a temperature lower (e.g., 37-39° C.) than that typically reached in an approach employing hyperthermia (Bassett et al., (1986) J. Urol. 135(3): 612-615; Needham et al., (2000) Cancer Res. 60(5): 1197-1201).
However, an approach for monitoring the release of liposome contents once an envirosensitive liposome has lost structural integrity has not been disclosed in the art. Therefore, absent a method of monitoring liposome opening and content release, a clinician or researcher must assume that the liposome was delivered to the desired site, that it ruptured and released its contents and that the contents were delivered to the desired site.
Thus, what is needed is an envirosensitive liposome, for example a thermosensitive liposome composition that exhibits a desirable phase transition at the typical temperature of hyperthermia (39-45° C.), or a radiation sensitive liposome that exhibits a desirable phase transition when contacted by a particular wavelength range of electromagnetic radiation (e.g., ionizing radiation). Further, what is needed is an envirosensitive liposome that is adapted to entrap a drug at a high concentration for long periods of time when maintained at physiological conditions, for example a temperature lower than that of hyperthermia for thermosensitive liposomes, and that is adapted to reliably release the drug efficiently at a desired site in a very short time after a particular environmental stimulation, for example at the temperature of hyperthermia or higher for thermosensitive liposomes. Such an envirosensitive liposome composition would also be adapted to be tracked to a desired location, wherein content delivery could be monitored in vivo by a non-invasive method.
What is also needed is a non-invasive method of monitoring tumor growth or regression, vascular morphology, vascular occlusion formation and dissolution, angiogenesis and wound healing in a subject that offers superior sensitivity, relative to the currently available methods. These and other problems are addressed by the compositions and methods disclosed herein.